This invention relates to an improved process for preparing a key intermediate useful in the synthesis of triazole antifungal compounds and other pharmaceutical compounds. In particular, the present invention provides an improved process for preparing a halomethyl benzoic acid chloromethyl ester which can be used, for example, to prepare triazole antifungal agents such as those described by our colleagues in co-pending U.S. Pat. No. 60/103,560 filed Oct. 7, 1998 and U.S. Pat. No. 6,265,584 issued Jul. 24, 2001, all of which applications being hereby incorporated by reference.
The intermediate, halomethyl benzoic acid chloromethyl ester, having the general formula ##STR1##
wherein X is Cl, Br or I and the halomethyl substituent is in the ortho, meta or para position of the phenyl ring is reported in the above-identified applications as being made by reacting the acid chloride of the formula ##STR2##
wherein X is as defined above with paraformaldehyde and zinc chloride in benzene. This method is also described by Iyer et. al. in Syn. Comm., 25, 2739, 1995. It suffers from several disadvantages, e.g. it is necessary to use benzene as the solvent and it requires a chromatography step.
The present inventors have discovered that the same acid chloride of the formula ##STR3##
wherein X is Cl, Br or I and the halomethyl substituent is in the ortho, meta or para position of the phenyl ring can be reacted with SnCl.sub.4 and 1,3,5-trioxane in an inert organic solvent such as methylene chloride to give key intermediate I in improved yields without many of the disadvantages of the above-mentioned process. For example, it is no longer necessary to use benzene as the solvent and the chromatography step is eliminated.
Intermediate I may be used to produce a number of biologically active products as illustrated below by its conversion to triazole antifungal agents.